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Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition
Hu Huang, … , John Jones, Young-Bum Kim
Hu Huang, … , John Jones, Young-Bum Kim
Published September 18, 2018
Citation Information: J Clin Invest. 2018;128(12):5335-5350. https://doi.org/10.1172/JCI63562.
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Research Article Endocrinology Metabolism Article has an altmetric score of 10

Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition

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Abstract

Obesity is a major risk factor for developing nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common form of chronic liver disease and is closely associated with insulin resistance, ultimately leading to cirrhosis and hepatocellular carcinoma. However, knowledge of the intracellular regulators of obesity-linked fatty liver disease remains incomplete. Here we showed that hepatic Rho-kinase 1 (ROCK1) drives obesity-induced steatosis in mice through stimulation of de novo lipogenesis. Mice lacking ROCK1 in the liver were resistant to diet-induced obesity owing to increased energy expenditure and thermogenic gene expression. Constitutive expression of hepatic ROCK1 was sufficient to promote adiposity, insulin resistance, and hepatic lipid accumulation in mice fed a high-fat diet. Correspondingly, liver-specific ROCK1 deletion prevented the development of severe hepatic steatosis and reduced hyperglycemia in obese diabetic (ob/ob) mice. Of pathophysiological significance, hepatic ROCK1 was markedly upregulated in humans with fatty liver disease and correlated with risk factors clustering around NAFLD and insulin resistance. Mechanistically, we found that hepatic ROCK1 suppresses AMPK activity and a ROCK1/AMPK pathway is necessary to mediate cannabinoid-induced lipogenesis in the liver. Furthermore, treatment with metformin, the most widely used antidiabetes drug, reduced hepatic lipid accumulation by inactivating ROCK1, resulting in activation of AMPK downstream signaling. Taken together, our findings establish a ROCK1/AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD.

Authors

Hu Huang, Seung-Hwan Lee, Inês Sousa-Lima, Sang Soo Kim, Won Min Hwang, Yossi Dagon, Won-Mo Yang, Sungman Cho, Min-Cheol Kang, Ji A. Seo, Munehiko Shibata, Hyunsoo Cho, Getachew Debas Belew, Jinhyuk Bhin, Bhavna N. Desai, Min Jeong Ryu, Minho Shong, Peixin Li, Hua Meng, Byung-Hong Chung, Daehee Hwang, Min Seon Kim, Kyong Soo Park, Maria Paula Macedo, Morris White, John Jones, Young-Bum Kim

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Figure 3

Loss of ROCK1 decreases hepatic lipid accumulation by reducing de novo lipogenesis.

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Loss of ROCK1 decreases hepatic lipid accumulation by reducing de novo l...
(A–E) Liver weight (A), liver triglycerides (B), liver cholesterol (C), H&E-stained liver sections (D), and in vivo fractional rate of triglycerides and glycerol in the liver (E) were measured in ROCK1loxP/loxP (control) and albumin-Cre;ROCK1loxP/loxP (L-ROCK1–/–) mice fed an HFD (n = 5−10 per group). Mice were fed an HFD from 6 weeks of age. Liver weight, liver triglycerides, and liver cholesterol were measured at 26 weeks of age. In vivo fractional rate of triglycerides and glycerol was measured from body weight–matched mice at 12 weeks of age. Scale bars: 100 μm. FSR, fractional synthesis rate. (F) In vivo fractional rate of triglycerides and glycerol in the liver were measured in control and L-ROCK1–/– mice fed a normal chow diet at 10–11 weeks of age (n = 4−5 per group). (G) Liver triglyceride and cholesterol content was measured in control and L-ROCK1–/– mice fed a normal chow diet at 18 weeks of age (n = 8−12 per group). (H and I) Fatty acid uptake (H) and fatty acid oxidation (I) were measured in isolated primary hepatocytes of body weight–matched control and L-ROCK1–/– mice fed an HFD at 12 weeks of age (n = 6 per group). (J) Serum triglyceride levels were measured after injection of poloxamer 407 solution in body weight–matched control and L-ROCK1–/– mice fed an HFD at 12 weeks of age (n = 7 per group). (K) Gene expression of key molecules involved in lipogenesis, gluconeogenesis, glycolysis, fatty acid oxidation, and uptake in the liver was measured by quantitative PCR in control and L-ROCK1–/– mice fed an HFD at 26 weeks of age (n = 5−8 per group). Values are means ± SEM. *P < 0.05 vs. control, **P < 0.01 vs. control by unpaired Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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